Capivasertib

1 INDICATIONS AND USAGE TRUQAP is a kinase inhibitor indicated: HR positive, HER2 negative locally advanced or metastatic breast cancer • in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN -alterations as detected by an FDA-authorized test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. ( 1.1 ) PTEN-deficient metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer • in combination with abiraterone and prednisone for the treatment of adult patients with metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer that is PTEN-deficient as detected by an FDA-authorized test. ( 1.2 ) 1.1 HR-positive, HER2-negative locally advanced or metastatic breast cancer TRUQAP, in combination with fulvestrant, is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN -alteration as detected by an FDA-authorized test following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. 1.2 PTEN-deficient metastatic androgen pathway modulation-naïve or -sensitive prostate cancer TRUQAP, in combination with abiraterone and prednisone, is indicated for treatment of adult patients with metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer that is PTEN-deficient as detected by an FDA-authorized test.

12.1 Mechanism of Action Capivasertib is an inhibitor of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3) and inhibits phosphorylation of downstream AKT substrates. AKT activation in tumors is a result of activation of upstream signaling pathways, mutations in AKT1 , loss of phosphatase and tensin homolog (PTEN) function and mutations in the catalytic subunit alpha of phosphatidylinositol 3-kinase ( PIK3CA ). In vitro , capivasertib reduced growth of breast cancer cell lines including those with relevant PIK3CA or AKT1 mutations or PTEN alteration. In vivo , capivasertib alone and in combination with fulvestrant inhibited tumor growth of mouse xenograft models including estrogen receptor positive breast cancer models with alterations in PIK3CA, AKT1 , and PTEN . In vitro , capivasertib reduced growth of AR-positive PTEN deficient prostate cancer cell lines. In vivo , capivasertib inhibited tumor growth in mouse xenograft models bearing PTEN-deficient prostate cancer cells and demonstrated increased antitumor activity when used in combination with abiraterone.

2 DOSAGE AND ADMINISTRATION • Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with TRUQAP based on the presence of one or more of the following genetic alterations in tumor tissue: PIK3CA/AKT1/PTEN . ( 2.1 ) • Select patients for the treatment of mAPMN/S prostate cancer with TRUQAP based on PTEN deficiency in tumor tissue. ( 2.1 ) • Recommended Dosage: 400 mg orally twice daily, with or without food, for 4 days followed by 3 days off. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with TRUQAP, based on the presence of one or more of the following genetic alterations in tumor tissue: PIK3CA/AKT1/PTEN [see Clinical Studies (14) ] . Select patients for the treatment of metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer with TRUQAP based on PTEN deficiency in tumor tissue [see Clinical Studies (14) ] . Information on FDA-authorized tests for patient selection for the detection of PIK3CA, AKT1, and PTEN alterations or PTEN deficiency are available at: http://www.fda.gov/CompanionDiagnostics 2.2 Recommended Evaluation Before Initiating TRUQAP Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C) prior to starting TRUQAP and at regular intervals during treatment [see Warnings and Precautions (5.1) ] . 2.3 Recommended Dosage The HR positive, HER2 negative locally advanced or metastatic breast cancer The recommended dosage of TRUQAP, in combination with fulvestrant, is 400 mg orally twice daily (approximately 12 hours apart) with or without food, for 4 days followed by 3 days off. Continue TRUQAP until disease progression or unacceptable toxicity. For premenopausal and perimenopausal women, administer a luteinizing hormone releasing hormone (LHRH) agonist according to current clinical practice standards. For men, consider administering a LHRH agonist according to current clinical practice standards. PTEN-deficient metastatic androgen pathway modulation-naïve or -sensitive (mAPMN/S) prostate cancer The recommended dosage of TRUQAP, in combination with abiraterone and prednisone, is 400 mg orally twice daily (approximately 12 hours apart) with or without food, for 4 days followed by 3 days off. Continue TRUQAP until disease progression or unacceptable toxicity. Patients with mAPMN/S prostate cancer should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Refer to the Prescribing Information of the individual therapeutic agents used in combination with TRUQAP for dosing and administration information. 2.4 Administration TRUQAP dosing schedule for each week is provided in Table 1. Table 1: TRUQAP Dosing Schedule for Each Week Day 1 2 3 4 5 No dosing on day 5, 6 and 7 6 7 Morning 2 x 200 mg 2 x 200 mg 2 x 200 mg 2 x 200 mg Evening 2 x 200 mg 2 x 200 mg 2 x 200 mg 2 x 200 mg Swallow TRUQAP tablets whole. Do not chew, crush, or split tablets prior to swallowing. Do not take tablets that are broken, cracked, or otherwise not intact. If a patient misses a dose within 4 hours of the scheduled time, instruct the patient to take the missed dose. If a patient misses a dose more than 4 hours of the scheduled time, instruct the patient to skip the dose and take the next dose at its usual scheduled time. If a patient vomits a dose, instruct the patient not to take an additional dose and take the next dose at its usual scheduled time. 2.5 Dosage Modification for Adverse Reactions The recommended dose reductions for adverse reactions are listed in Table 2. Permanently discontinue TRUQAP if unable to tolerate the second dose reduction. Table 2: Recommended Dose Reductions of TRUQAP for Adverse Reactions TRUQAP Dose and Schedule First dose reduction 320 mg twice daily for 4 days followed by 3 days off Second dose reduction 200 mg twice daily for 4 days followed by 3 days off The recommended dosage modifications for

6 ADVERSE REACTIONS The following adverse reactions are also discussed in greater details in other sections of the labeling: • Hyperglycemia [see Warnings and Precautions (5.1) ] • Diarrhea [see Warnings and Precautions (5.2) ] • Cutaneous Adverse Reactions [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥20%), including laboratory abnormalities, in patients with: • HR-positive, HER2-negative breast cancer were diarrhea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting and stomatitis. ( 6.1 ) • PTEN-deficient mAPMN/S prostate cancer were increased fasting glucose, decreased hemoglobin, decreased lymphocytes, cutaneous adverse reactions, diarrhea, decreased potassium, increased creatinine, increased non-fasting glucose, increased alanine aminotransferase, increased triglycerides, increased aspartate aminotransferase, decreased sodium, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in WARNINGS and PRECAUTIONS reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with fulvestrant, in 355 patients with metastatic breast cancer in CAPItello-291 until disease progression or unacceptable toxicity. Among the 355 patients who received TRUQAP in combination with fulvestrant, 52% were exposed for 6 months or longer, and 27% were exposed for greater than one year. In this safety population, the most common (≥ 20%) adverse reactions including laboratory abnormalities were diarrhea (72%), cutaneous adverse reactions (58%), increased random glucose (57%), decreased lymphocytes (47%), decreased hemoglobin (45%), increased fasting glucose (37%), nausea and fatigue (35% each), decreased leukocytes (32%), increased triglycerides (27%), decreased neutrophils (23%), increased creatinine (22%), vomiting (21%), and stomatitis (20%). The safety population described in WARNINGS and PRECAUTIONS also reflects exposure to TRUQAP 400 mg orally, twice a day for 4 days followed by 3 days off, in combination with abiraterone, in 503 patients with mAPMN/S prostate cancer with PTEN deficiency in CAPItello-281 until disease progression or unacceptable toxicity. CAPItello-291 The safety of TRUQAP was evaluated in CAPItello-291, a clinical trial including 288 adult patients (155 patients in TRUQAP with fulvestrant arm and 133 patients in placebo with fulvestrant arm) whose breast cancer had one or more PIK3CA/AKT1/PTEN -alterations [see Clinical Studies (14) ] . Among patients who received TRUQAP, 61% were exposed for 6 months or longer and 30% were exposed for greater than one year. Of the 155 patients who received TRUQAP with fulvestrant, the median age was 58 years (range 36 to 84); female (99%); White (48%), Asian (31%), Black (1.3%), American Indian/Alaska Native (0.6%), and other races (19%). Serious adverse reactions occurred in 18% of patients receiving TRUQAP with fulvestrant. The most common serious adverse reactions (≥ 1%) were cutaneous adverse reaction (3.9%), diarrhea and pneumonia (2.6% each), vomiting and pyrexia (1.9% each), hyperglycemia, hypersensitivity, fatigue, renal injury and second malignancy (1.3% each). Fatal adverse reactions occurred in 1.3% of patients who received TRUQAP with fulvestrant, including sepsis (0.6%), and acute myocardial infarction (0.6%). Permanent TRUQAP discontinuation due to an adverse reaction occurred in 10% of patients.

5 WARNINGS AND PRECAUTIONS • Hyperglycemia: TRUQAP can cause severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes. Evaluate blood glucose levels and hemoglobin A1C prior to starting and at regular intervals during treatment. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. ( 2.2 , 2.5 , 5.1 ) • Diarrhea: TRUQAP caused diarrhea in most patients. Advise patients to increase oral fluids, start antidiarrheal treatment, and consult with a healthcare provider if diarrhea occurs while taking TRUQAP. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. ( 2.5 , 5.2 ) • Cutaneous Adverse Reactions: Monitor for signs and symptoms of cutaneous adverse reactions. Withhold, reduce dose, or permanently discontinue TRUQAP based on severity. ( 2.5 , 5.3 ) • Embryo-Fetal Toxicity: TRUQAP can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information. ( 5.4 , 8.1 , 8.3 ) 5.1 Hyperglycemia TRUQAP can cause severe hyperglycemia, including diabetic ketoacidosis and fatal outcomes. Withhold TRUQAP in clinical situations known to increase the risk of severe hyperglycemia or ketoacidosis (e.g., suspected serious infection or acute illness). Before initiating treatment with TRUQAP, test fasting glucose levels (FPG or FBG), HbA1C levels, and optimize fasting glucose. After initiating treatment with TRUQAP, monitor or self-monitor fasting glucose levels on Day 3 or 4 of the dosing week during weeks 1, 2, 4, 6 and 8; then monthly while on treatment with TRUQAP; and as clinically indicated. Monitor HbA1C levels every 3 months during treatment with TRUQAP and as clinically indicated and manage changes as appropriate. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and require close monitoring of fasting glucose levels. For patients who experience hyperglycemia during treatment with TRUQAP, monitor fasting glucose at least twice weekly, on days on and off TRUQAP, until fasting glucose decreases to baseline levels. During treatment with anti-diabetic medications, monitor fasting glucose at least once a week for 2 months, followed by once every 2 weeks, or as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and initiation of fasting glucose monitoring at home for patients who have risk factors for hyperglycemia or who experience hyperglycemia. Advise patients of the signs and symptoms of hyperglycemia and counsel patients on lifestyle changes. Withhold TRUQAP immediately when ketoacidosis is suspected. If ketoacidosis is confirmed, permanently discontinue TRUQAP. The safety of TRUQAP has not been established in patients with Type 1 diabetes or Type 2 diabetes that is uncontrolled or requiring insulin at baseline as these patients were excluded from clinical studies [see Clinical Studies ( 14.1 , 14.2 )] . Based on the severity of the hyperglycemia, withhold, reduce dose, or permanently discontinue TRUQAP [see Dosage and Administration (2.5) ]. CAPItello 291 Increased fasting glucose from baseline occurred in 37% of patients treated with TRUQAP, including 11% of patients with Grade 2 (FG > 160 to 250 mg/dL), 2% with Grade 3 (FG > 250 to 500 mg/dL), and 1.1% with Grade 4 (FG > 500 mg/dL) events. The median time to first occurrence of hyperglycemia was 15 days (range: 1 to 367). Dose reduction for hyperglycemia was required in 0.6% of patients and permanent discontinuation was required in 0.6% of patients. Diabetic metabolic decompensation occurred in 0.6% of patients, including diabetic ketoacidosis in 0.3%. In CAPItello-291, 12% (43/355) of patients who received TRUQAP had an anti-hyperglycemic medication regimen either initiated or changed during the study, including treatment with insulin in 4.8% (17/355) o

4 CONTRAINDICATIONS TRUQAP is contraindicated in patients with severe hypersensitivity to TRUQAP or any of its components. Severe hypersensitivity to TRUQAP or any of its components. (4)